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Airway epithelial cells, the first barrier of the respiratory tract, play an indispensable role in innate immunity. Integrin β4 (ITGB4) is a structural adhesion molecule that is involved in the pathological progression of acute inflammatory diseases and is downregulated in asthmatic patients. Research has shown that endothelial ITGB4 has proinflammatory properties in acute lung injury (ALI). However, the role of epithelial ITGB4 in a murine ALI model is still unknown. This study investigated the role of ITGB4 in lipopolysaccharide (LPS)‐induced ALI. We found that ITGB4 in the airway epithelium had remarkably increased after the introduction of LPS in vivo and in vitro. Then, we constructed airway epithelial cell‐specific ITGB4 knockout (ITGB4−/−) mice to study its role in ALI. At a time point of 12 h after the tracheal injection of LPS, ITGB4−/− mice showed increased macrophages (mainly M1‐type macrophages) and neutrophil infiltration into the lungs; inflammation‐related proteins including interleukin (IL)‐6, tumor necrosis factor, and IL‐17A were significantly elevated compared to their levels in ITGB4+/+ mice. Furthermore, we investigated the role of ITGB4 in the anti‐inflammatory response. Intriguingly, in the ITGB4−/− + LPS group, we found significantly reduced expression of anti‐inflammatory factors, including IL‐10 messenger RNA (mRNA) and ARG‐1 mRNA. We also observed that monocyte chemotactic protein (MCP‐1) increased significantly both in vivo and in vitro. Airway epithelium activates macrophages, most likely driven by MCP‐1, which we confirmed in the coculture of epithelia and macrophages. These phenomena indicate that ITGB4 in airway epithelial cells plays an important role in the process of inflammation and activation of macrophages in ALI. Overall, these data demonstrated a novel link between airway epithelial ITGB4 and the inflammatory response in LPS‐induced ALI. [ABSTRACT FROM AUTHOR]

Accumulated research has suggested the importance of the adhesion molecules modulation as therapeutic approach for bronchial asthma. Adhesion molecules expression alteration contributes to the pathogenesis of asthma. In order to probe the roles of expression imbalance of adhesion molecules in asthma pathogenesis, expression profiling of adhesion molecules was performed using cDNA microarray assay. The results showed that the expression pattern of adhesion molecules was altered in peripheral blood leucocytes of asthma patients. In this study, we focused on one of the abnormally expressed molecule, integrin β4, which was down-regulated in all asthma patients, to analyze the relevance of asthma susceptibility with the alteration of integrin β4 expressions. Real time PCR was used to verify the down-regulation of integrin β4 in additional 38 asthma patients. Next, the 5′flanking region of integrin β4 DNA were amplified, sequenced and site-directed mutagenesis technology in correspondent variation sites were carried out. Among 4 variation sites found in 5′ flanking region of integrin β4, 3 were related to asthma susceptibility: -nt1029 G/A, -nt 1051 G/A, and -nt 1164 G/C. A reduction of human integrin β4 promoter activity was observed at mutants of these sites. This study demonstrates that various adhesion molecules in asthma patients are abnormally expressed. Mutations in 5′ flanking region result in reduced integrin β4 expression, which is related to increased risk of asthma. [ABSTRACT FROM AUTHOR]

Abstract: It is known that ozone stress can induce airway hyperresponsiveness (AHR). The underlying cellular and molecular mechanisms are not fully understood. We constructed a successive ozone-stressed rat model and showed that AHR caused by ozone stress presented as increased lung resistance (R L) to inhaled histamine but not baseline R L. Meanwhile, structural disruption and decreased expression of integrin β4 on airway epithelia were observed. Further regression analysis revealed a significant negative correlation between increases in R L to histamine (at 0.32mg/ml) and mRNA expression of integrin β4. Moreover, when integrin β4 on human bronchial epithelial cells was knocked down, we found that reactive oxygen species was increased and apoptosis rates were higher. Overall, this study suggests that downregulation of integrin β4 is important for the development ozone stress-induced AHR, presumably because it causes increased oxidative damage and epithelial apoptosis. [Copyright &y& Elsevier]